1. Field of the Invention
The present invention relates generally to the field of chemical synthesis. More particularly, it concerns methods for preparation of chirally pure epoxide.
2. Description of Related Art
Epoxides are very important synthetic intermediates for variety of biologically active and other synthetic molecules. These are key intermediates for preparation of chirally pure β-amino alcohols used as β-blockers (Enzyme Microb. Technology 1993, 15, 266; J. Med. Chem. 2002, 45, 567; Org. Lett. 2002, 4, 3793; Synlett 2005, 12, 1948; J. Chem. Tech. Biotech. 1996, 66, 233), different antibiotics (J. Am. Chem. Soc. 1981, 103, 464), neuroprotective agents (Bioorganic and Medicinal Chemistry Lett. 1995, 5, 551), antidepressants (Tetrahedron: Asymmetry 2002, 13, 2039) apart from serving as important precursor for the production of a variety of natural and clinical products. It is for these reasons studies have been on the run for asymmetric synthesis of epoxides from olefins through chemical and biochemical means. Chiral epoxides whether produced from olefins or other sources have the advantage as electrophilic intermediates for stereochemical synthesis involving reactions with nucleophiles. The present invention relates to a new method of producing chiral induction to styrene oxides and its derivatives and other chiral epoxides from the corresponding olefinic compounds using 2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid monohydrate, which is otherwise used in its ester form for racemic modification of optically active amines through formation of diastereomeric salts (U.S. Pat. No. 3,855,227, Den Hollander, Charles William). This approach can be used in efficient synthesis of members of a large family of chiral intermediates without the need to design custom chiral synthesis for each new compound. The method conforms to the Roundtable suggestion chalked out in the ACS and Global Pharmaceutical industries meet held during 2005 (Green Chemistry, 2007, 9, 411).
The prior art shows that preparation of various chiral epoxides from styrene derivatives and other olefinic compounds has been accomplished employing various strategies using chemical catalysts or biological catalysts.
A. Chemical Synthesis
1. Yian Shi; Acc. Chem. Res. 2004, 37, 488 and References Cited Therein.
Chiral ketones more particularly carbocyclic analogues of fructose of the structural formula ‘5’ have been shown to be effective organocatalysts for asymmetric epoxidation of cis & trans olefins represented by the structural formula ‘3’ wherein R1 is selected from the group consisting of alkyl, alicyclic, aryl, R2 is selected from the group consisting of H, alkyl, and R3 is selected from the group consisting of H, alkyl, allyl, carboxylic, etc.

The disadvantage of this method is that it is highly pH dependent and the catalyst undergo decomposition through Baeyer-Villiger oxidation in presence of oxone.
2. C. Marchi-Delapierre, A. Jorge-Robin, A. Thibon and S Menage; Chem. Commun., 2007, 1166.
Different olefins including electron deficient systems, undergo epoxidation at 0° C. in presence of a per-acid under the catalytic influence of dinuclear chiral complex Fe2O(bis PB)4(X)2(ClO4)4 (X=H2O or CH3CN) ‘8’ whereby a moderate enantioselectivity (9-63%) and yield were achieved.

The disadvantage is that per acid used is expensive and unstable and the iron catalyst is to be specially designed.
3. E. M. McGarrigle and Declan G. Gilheamy; Chemical Review, 2005, 105, 1563.
A number of chromium and manganese metal salen complex represented by the general structural formula ‘9’ wherein ‘M’ represents chromium or manganese have been reported to produce chirally pure epoxides (ee, 50-90%) from different substituted and unsubstituted olefins in presence of sodium hypochlorite oxidant.

However, the catalyst is required to be specially designed and possesses environmental problems.
4. Hua Yi, G Zou, Q. Li, Q Chen, J. Tang and M.-Y. He; Tetrahedron Lett., 2005, 46, 5665.
α/β-Unsaturated ketones represented by the structural formula ‘10’ in which ‘R1’ consists of Ph, p-MeOC6H4, p-O2NC6H4, o-MeOC6H4, o-EtOC6H4, p-ClC6H4 and ‘R2’ consists of Ph, o-MeOC6H4, p-ClC6H4 etc. undergo Julia-Colonna asymmetric epoxidation in the olefinic bond in presence of silica grafted poly-(L)-leucine catalyst and hydrogen peroxide with moderate to good enantioselectivity.

The disadvantage of this method is that it is limited to α,β-unsaturated systems only.
5. A. H. Hoveyda; Chem. Rev., 1993, 93, 1307.
In this report olefinic compounds or chiral olefinic compounds having scope for specific binding with per-acid has been described. However, per-acid as such is expensive and unstable and unsafe for handling.
6. D. Chaterjee, S. Basak, A. Riahi and J. Muzart; Catalysis Commun. 2007, 8, 1345.
Chaterjee et. al. developed one catalyst MnIII[(TDLi+)(PIC)(H2O)] represented by the structural formula ‘12’ where TDLi stands for N-3,5-di-(t-butyl) salicylidine-D-glucosamine and PIC stands for picolinate in presence of which different styrene derivatives, methylcyclohexene, 1,2-dihydronaphthalene were transformed into chirally pure epoxides using t-butylhydroperoxide oxidant. The enantioselectivity and product yield have been found to be 52-68% and 8-54% respectively.

From the environmental aspect point of view, the yield and also the enantioselectivity achieved above, the use of the metal complex catalyst is not desirable.
7. H. Kakei, R. Tsuji, T. Ohshima and U. Shibasaki; J. Am. Chem. Soc., 2005, 127, 8962.
This method describes chiral epoxidation of α/β-unsaturated methyl ester with good yield (62-97%) and enantioselectivity (89-99%) in presence of yttrium-biphenyldiol complex represented by the structural formula ‘13’ and t-butylhydroperoxide.

However, the complex catalyst is not environment friendly.
8. C.-Y. Ho, Y.-C Chen, M.-K Wong and D. Yang; J. Org. Chem. 2005, 70, 898.
Here in this method asymmetric epoxidation of various olefins has been reported in presence of different chiral cyclic secondary amines represented by the structural formula ‘16’ under the oxidizing influence of oxone wherein R represents phenyl, p-tolyl, 1-naphthyl, 2-naphthyl, 4-phenylphenyl, 2,4-difluorophenyl, 3,5-di(trifluoromethyl)phenyl, R1=F, OH, OMe, R2=H, F and observed that amines having fluorine substituent at the -position relative to amine center has been found to give highest enantiomeric excess of 61% with 92% yield.

The drawback of this method is that the catalyst used is not eco-friendly and is not recyclable.
9. J. Vachon, C. Perollier, D Monchaud, C. Marsol, K. Ditrich and J. Lacour; J. Org. Chem. 2005, 70, 5903.
Vachon et. al. reported a catalytic system chiral iminium TRISPHAT [tris (tetrachlorobenzenediolato)phosphate(V)] salt combining a diphenylazepinium core represented by the structural formula ‘17’ wherein R1 & R2 consists of H, alkyl, aryl group, chiral exocyclic appendages and a lipophilic counterion for biphasic chiral epoxidation of olefins of the formula ‘18’ in which R1 represents H, alkyl, aryl, R2 represents H, alkyl, phenyl, naphthyl and R3 represents phenyl, R2═R3═—(—C6H4(CH2)2— or R2═R3═—(CH2)6—.
From the cost and environmental point of view the catalysts is expensive, is to be specially designed and not friendly.

10. M. Marigo, J. Franzen, T. B. Poulsen, W. Zhuang and K. A. Jorgensen; J. Am. Chem. Soc., 2005, 127, 6964.
This is an attractive method for asymmetric epoxidation of α,β-unsaturated aldehyde with H2O2, t-BuOOH or UHP in presence of chiral bisaryl silyl protected pyrrolidine ‘22’ to have enantiomeric excess and diasteriomeric ratio to be more than 92 and 93:7.

However the method is limited to α,β-unsaturated aldehyde only.
11. O. Bortolini, G. Fantin, M. Fogagnolo and L. Mari, Tetrahedron, 2006, 62, 4482.
Few 3-keto bile acid derivatives ‘23’ have been evaluated in the asymmetric epoxidation of unfunctionalized olefins represented by the structural formula ‘1’ in which R1 consists of Ph, Tolyl, R2 consists of H, methyl, R3 consists of H, methyl, phenyl or ‘1’ represents 1,2-dihydronaphthalene with oxone up to 98% ee has been achieved by this method.

However, the catalyst availability is limited.
12. T. Geller, A. Gerlach, C. M. Kruger and H. Christian Militzer; Tetrahedron Lett., 2004, 45, 5065.
This is an improvement of Julia-Colonna epoxidation of α,β-unsaturated ketone upon addition of a phase transfer catalyst yielding chiral, nonracemic epoxy ketones. The reaction is treatment of α,β-unsaturated ketone with H2O2 and poly L-leucine ‘26’ in presence of tetrabutyl ammonium bromide (TBAB) as phase transfer catalyst that triggers acceleration of the reaction with 99% convertion and 94% enantiomeric excess.


As stated, the reaction is limited to α,β-unsaturated system.
13. X. Liu, Y. Li, G. Wang, Z. Chi, Y. Wu and G. Zhao; Tetrahedron: Asymmetry, 2006, 17, 750.
α,β-Unsaturated ketones can also be epoxidized under mild protocol using chiral pyrrolidinyl methanol ‘27’ as dendritic catalysts and t-butylhydroperoxide as oxidant.

But the catalyst design is troublesome.
14. W. Zhang, J. L. Loebach, S. R. Wilson, E. N. Jacobsen; J. Am. Chem. Soc., 1990, 112, 2801 and W. Zhang, E. N. Jacobsen; J. Org. Chem., 1991, 56, 2296.
Here it is used (Salen) manganese complex ‘28’ for enantioselective epoxidation of unfunctionalized olefins using NaOCl with 86% yield.

The catalyst is however not environment friendly.
15. Kazuhide Tani, Masayoshi Hanafusa, Sei Otsuka; Tetrahedron Lett., 1979, 20, 3017.
Prochiral squalene has been chirally epoxidized with t-BHP and Mo (VI) catalysts in presence of optically active diols.

However, use of metal complex catalyst is not desirable.
16. J. Lv, X. Wang, J. Liu, L. Zhang and Y. Wang; Tetrahedron: Asymmetry, 2006, 17, 330.
Chiral epoxidation with 86% ee and 54-96% yield has been achieved using dimeric cinchonine, chinconidine and quinine anchoring to long linear PEG chain ‘31’.

However, the catalyst availability is poor.
17. G. Paris, C. E. Jacobsche and S. J. Miller; J. Am. Chem. Soc., 2007, 129, 8710.
This is another report of epoxidation using organic catalyst aspertate derivatives ‘32’ having a peptide sequence through per-acid formation of aspertic carboxylic group with hydrogen peroxide in presence of either 4-N,N-dimethyl amino pyridine (DMAP or NMO with 76-89% ee and 80-95% isolated yield.

18. J. Legros, B. Crousse, D. Bonnet-Delpon and J.-P. Begue; Eur. J. Org. Chem., 2002, 3290.
This is a report for achiral epoxidation of olefin using fluoroketone ‘33’ as catalyst in presence of UHP in hexafluoro-2-propanol with good yield.

However, no chiral purity is achieved in the products.
19. M. F. A. Adamo, V. K. Agarwal and M. A. Sage; J. Am. Chem. Soc., 2000, 122, 8317.
Agarwal et. al. reported another chiral epoxidation of olefins using amine catalyst more particularly chiral pyrrolidine derivative ‘34’ and found to be better in yield and enantioselectivity compared to methyl trioxorhenium catalyst (MTO).

20. F. Bjorkling, S. E. Godtfredsen and O. Kirk; J. Chem. Soc. Chem. Commun., 1990, 1301.
Bjorkling et. al reported the preparation of different epoxides acyclic and cyclic olefins using a fatty acid such as octanoic acid as oxygen carrier through in situ formation of its per-acid with hydrogen peroxide under the catalytic influence of lipase from different species with moderate to good yields. However no chirally pure could be isolated from this method.
21. K, Sarma, N Bhati, N Borthakur and A. Goswami, Tetrahedron, 2007, 63, 8735.
In this method chirally pure epoxide preparation from different olefins was reported using Urea-Hydrogen peroxide adduct and N-2,4-dinitrophenyl-L-proline in presence of lipase from Pseudomonas species G6 [PSLG6] with good yield and enantiomeric excess.
B. Enzyme Catalysis
Biological catalysts have been employed for epoxidation using pure enzyme or whole cell microbes. Oritg de Montellano et al.; J. Am. Chem. Soc., 1991, 113, 3195; D. R. Boyd, N. D. Sharma and A. E. Smith; J. Chem. Soc. Perkin Trans. 1, 1982, 2767 and V. Schurig, D. Wistuba; Angew. Chem. Int. Ed. (Engl.), 1984, 23, 796.
1. Using Cytochrome P-450
Cytochrome P-450 monooxygenase family has been used as epoxidation catalysis both with purified enzymes isolated from mammalian, microbial and plant sources and with partially purified liver microsomal preparation. The stereochemical course and the enantioselectivity of the P-450 reactions have been examined in some instances.
Wislocki and Lu.; Proc. Natl. Acad. Sci. USA 79, 1982, 6802. In this study the epoxidation of 8-methyl benz[a]anthracene has been reported using Cytochrome P-450 and P-448 and showed epoxidation at different faces of 8,9-double bond.
P. R. Ortiz de Montellano, B. L. Mangold, C. Wheeler, K. L. Kunze and N, O. Reich; J. Biol. Chem., 1983, 258, 4208. Octene on epoxidation with Cytochrome P-450 gave S(−) enantiomer of the epoxide formed in the little excess over the R(+) isomer. Thus ee is poor.
2. Liver Microsomes
D. Wistuba, H.-P. Nowotny, O. Trager, V. Schurig; Chirality, 1989, 1, 127. Partial enantioselectivity (50% ee) has been observed in aliphatic alkene epoxides by liver microsomes. Since Cytochrome P-450 needs continuous supply of cofactors NADH such enzymes are not suitable for large scale synthesis.
3. Other Enzymes
J. H. Capdevila, A. Karara, D. J. Waxman, M. V. Martin, J. R. Falck and F. P. Guenguerich; J. Biol. Chem. 1990, 265, 10865. Methymoglobin and metmyoglobin catalyse the hydrogen peroxide depended oxidation of styrene to styrene oxide and benzaldehyde but with no enantiomeric excess.
4. Horseradish Peroxidase
P. R. Ortiz de Montellano, L. A. Grab; Biochemistry, 1987, 26, 5310. HR peroxidase is capable of catalyzing the oxidation of styrene when supplemented with hydrogen peroxide and oxidizable phenol. The key features of the reactions involve first the oxidation of the phenol to a free radical which in turn reacts with molecular oxygen to generate the peroxy radical. The peroxy radical then reacts with styrene to form the epoxide.
The problem encountered with these catalysts is that availability is limited.
5. By Chloroperoxidase
P. R. Ortiz de Montellano, Y. S. Choe, G. DePillis and C. E. Catalano; J. Biol. Chem., 1987, 262, 11641. (i) Chloroperoxidase (CPO) and Cytochrome P-450 function similarly in the epoxidation and N-demethylation reactions. However, CPO utilizes H2O2 whereas the P-450 utilize molecular oxygen and require a regenerable reducing reagent usually NADH. The CPO and H2O2 oxidize styrene to styrene oxide and phenylacetyldehyde showed that trans epoxide is the major product.
L. P. Hager, E. J. Allan; U.S. Pat. No. 5,358,860, 1994. Here in this report olefin have been shown to epoxidize with H2O2 at pH 5 with good yield and 97% enantiomeric excess. But, due to very high cost of the enzyme and limited availability, the process is less meritorious.
A. W. P. Jarvie, N. Overton and C. B. St Pourcain; Chem. Commun., 1998, 177. In this report epoxidation of phenylpolybutadiene has been reported to be done by Immobilized lipase and H2O2 in presence of acetic acid where 1,4-trans and 1,4-cis epoxy phenyl polybutadiene formed leaving behind 1,2-vinyl group in CH2Cl2 with poor yield (21-31%).
Dr. F. A. I. Vidal; N. Nieto Alonso; Dr. P. Molar Porqueras; European patent, EP 1770094. Here in this patent electron deficient alkenes have been reported to be epoxidized by dioxirane chiral ketone generated from oxone starting from D-fructose.
C. By Cell Cultures
1. H. Ohta and H. Tetsukawa; J. Chem. Soc. Chem. Commun., 1978, 849.
In this report, conversion of alkenes viz. hexadec-1-ene to R(+) epoxide by whole cell culture of microorganism from Coryniebacterium equi has been studied.
2. D. I. Sterling and H. Dalton; FEMS Microbiology Letters, 1979, 5, 315.
Stirling and Dalton have shown that whole cell cultures of Methylococcus Capsulatus (Bath) are capable of converting ethylene, propylene, 1-butene and cis and trans-2-butene to epoxides when supplied with formaldehyde as co-substrate.
3. M.-J. D E Smet, H. Wynberg and B. Witholt; Applied and Environmental Microbiology, 1981, 42, 811.
D E Smet et. al. have shown that under optimum conditions, resting and growing cultures of Pseudomonas oleovarans convert 1-octene to 1,2-epoxyoctane.
4. H. Fu, M. Newcomb, C. H. Wong; J. Am. Chem. Soc., 1991, 113, 5878.
In this report, Fu et. al. have shown that Pseudomonas oleovarans cultures were unable to oxidize internal olefins and distributed terminal olefins.
In short, it may be noted that despite substantial efforts throughout the world, to have benign method for epoxidation of olefins, several lacunae are therein and needs extensive work for eco-friendly epoxidation of olefins using organic or bioorganic catalysts.